Carcinogenesis Flashcards
found in all progeny, begins the process towards malignant transformation
Initiating mutation
- Essentially the first driver mutation
- Often include loss-of-function mutations in genes that maintain genomic integrity
mutation that increases
malignant potential of the cell
Driver mutation
mutation with low malignant
effect
Passenger mutation
Mutations that result in the attributes of malignant cells include:
excessive growth, local invasion, distant
metastasis
Gain-of-function mutations
increasing in function - functioning more than it typically would in a normal person
Proto-oncogenes
Generally loss-of-function mutations
Tumour suppressor genes
class of mutated genes that can be gain- or loss-of-function
Genes regulating apoptosis
what class of mutated genes are genes responsible for DNA repair?
- Generally loss of function
- Affected cells acquire mutations at an accelerated rate (aka genomic instability)
Once established, tumours evolve genetically based on ____________. This results in tumour cells being genetically ______________.
survival/selection of the fittest (only the best mutations win)
- Resulting in tumour cells being genetically heterogeneous
Tumour subclones compete for access to _________ with the fittest subclones dominating tumour mass
nutrients
As a result, tumours become more aggressive over time
Tumours that recur after therapy are almost always found to be _________ to the initial treatment
resistant
what type of mutation class promotes excessive cell growth, even in the absence of normal growth-promoting signals
Mutation class - Oncogenes
how are oncogenes created?
- created by mutations in proto-oncogenes (unmutated cellular counterparts)
genes that normally help cells grow and divide to make new cells, or to help cells stay alive.
Proto-oncogenes
growth factors or their receptors, signal transducers, transcription
factors, or cell cycle components
can be mutated and become an oncogene
- Ras
- PI3 K
- Myc
- Cyclins and cdks
are all examples of?
proto-oncogenes
BRAF - point mutation, translocation - melanomas, leukemias, colon carcinoma and others
RAF
Transcriptional activators - translocation - Burkitt lymphoma
MYC
CCND1
CDK4
Downstream component of receptor tyrosine kinases signaling pathways
RAS
what is the single most
common abnormality of proto-oncogenes in human tumors
Point mutation of RAS family genes
RAS causes
____ of pancreatic adenocarcinomas and
cholangiocarcinomas
____ of colon, endometrial, and thyroid cancers
____ of lung adenocarcinomas and myeloid leukemias
90%
50%
30%
Important downstream signaler for lots of growth factors. What are some examples?
RAS
* EGF, PDGF, and CSF-1
Ras leads to the activation of what? This induces what type of transcription factors
Ras leads to the activation of MAP kinase which induces MYC
MYC induces cyclin, more cyclin = less checkpoints resulting it increased cell proliferation
What does PI3 induce?
AKT
what does AKT do?
AKT can promote cell cycle progression by activating cyclin A (CDK-1 for S phase) and cyclin D = increase in checkpoints
what does AKT decrease/inactivate?
p21 and p27
these are important for inhibiting cyclins (inhibits apoptosis)
Immediate early response gene. Induced by Ras/MAPK signaling
MYC (transcription factor)
when increased, what does MYC do?
Increases cell proliferation & growth
Contributes of other hallmarks of cancer
- Warburg effect (eg. can upregulate glycolytic enzymes)
- increased telomerase activity (contributes to endless
replicative activity)
- May also allow more terminally differentiated cells to
gain characteristics of stem cells
what is the Warburg effect
glycolytic enzymes are upregulated
- in this case, cancer cells choose pyruvate to lactic acid pathway for energy even though there is an abundance of oxygen
increase _________ activity contributes to endless replicative activity
telomerase
MYC is implicated in cancers of (3)
breast, colon, lung
Which of the two cell cycle checkpoints regulated by CDK-cyclin complexes do you suppose is more important in cancer?
G1/S
- is the start transition
- if you can get it going and going rapidly, then it allows for more success
MORE mutations will be affiliated with the aspects that are checked at G1/S
Products of _________________ apply brakes to cell proliferation. Therefore, abnormalities lead to..?
tumour suppressor genes
lead to failure of growth inhibition
Rb, P53 and CKIs are examples of which mutation class gene?
Mutation class - Tumour suppressor
genes
Activation of oncogenes isn’t enough for cancer induction, usually requires loss of _____________ genes as well
tumour suppressor
in a normal cell, RB and p52 recognize genotoxic stress and respond by…
responds by shutting down proliferation
RB
CDKN2A
TP53
the guardian of the genome
Which tumour suppressor gene functions as a key negative regulator of the G1/S checkpoints
RB
when is RB in its active form?
when it is hypophosphorylated
what E2F induce?
transcription factors in the S phase
what form is RB in to facilitate passing through the G1/S checkpoint?
hyperphosphorylated (inactive)
what is gene considered the guardian of the genome and codes for p53 protein. This is also the most frequently mutated gene in human cancer
- TP53
what is the function of TP53?
Regulates cell cycle progression, DNA repair, cellular senescence, and apoptosis
what is P53 usually bound to?
Mdm2
what does p53 induce synthesis of?
p21 - binds cell cycle progression
- p21 binds to CDKS (check-point proteins) to inactive that
this stops the cell cycle so that the DNA repair cell can be repaired
P53 uses _____ and _____ for successful DNA repair
p21 and GADD45
what will occur in a cell with mutations of loss of p53
there will be no cell cycle arrest, no DNA repair, no senescence
this will result in mutant cells and ultimately the expansion and additional mutations
how does p53 arrest the cell cycle until DNA can be repaired?
p53 induces the synthesis of p21 which binds to and inhibits CDKs - to stop it from working as a result, this stops the cycle cell
____ can also be silenced by hypermethylation rather than mutation. This is an example of a ________ change and occurs in some cervical cancers
p16 - by silenced by hypermethylation
Inhibits Cdk4- Cyclin D complex (G1-CDK complex) needed for progression through the cell cycle - describes the function of what
p16
What do you notice about the common oncogenes and tumour suppressor genes we have discussed?
G1/S
start transition
At least 1 of the 4 key regulators of the cell cycle is dysregulated in the significant majority of all human cancers
p16, cyclin D, Cdk4, RB
The wnt-B-catenin pathway normally promotes
cell-proliferation
mutation in APC
excessive activity (gain of function of) of B-catenin
All cancers display 8 fundamental changes in cell physiology:
- Self-sufficiency in growth signals
- Insensitivity to growth-inhibitory signals
- Altered cellular metabolism
- Evasion of apoptosis
- Limitless replicative potential
- Sustained angiogenesis
- Ability to invade and metastasize
- Ability to evade the host immune system
Cancer cells take up high levels of glucose and
demonstrate increased conversion of glucose to lactate. Even in the presence of ample oxygen
Warburg effect
Why do you suppose a cancer cell relies on glycolysis alone for ATP production?
it uses the byproduct of glycolysis as the building blocks for quick growth
Mitochondrial oxidative phosphorylation does not!
cell permanently exits the cell cycle & never divides again
Senescent
how can cancer cells evade senescence
- Likely due to loss of functions mutations in p53 and p16
- Allows cell to pass through G1/S checkpoint
Cancer cells have also demonstrated the ability to express telomerase. what does this allow the cancer cell to do?
Remember telomerase is only very minimally expressed in most somatic cells
replicate indefinitely
